A continuous DNA repairing system for alleviating intervertebral disc degeneration

DNA damage triggering senescence-associated secretory phenotype (SASP) is a key pathway of Intervertebral Disc Degeneration (IVDD). Current therapeutic strategies for IVDD face significant challenges in effectively alleviating DNA damage-mediated senescence of nucleus pulposus cells (NPCs) and IVDD repair. Here, we propose a strategy for the continuous regulation of DNA repair: starting with the scavenging of the key upstream trigger, ROS, proceeding to the repair of the DNA damage, and culminating in the promotion of DNA replication and extracellular matrix synthesis. Through single-cell sequencing of clinical samples and in vitro modeling, we elucidated how oxidative stress drives DNA damage, leading to SASP and inflammatory microenvironment within the intervertebral disc. Subsequently, we developed a continuous DNA repairing system. In this system, bimetallic-curcumin nanozymes (AuCu-Cur) scavenge ROS in NPCs and repair damaged DNA via the increased DNA glycosylase NEIL3. Additionally, the combined human umbilical cord-derived vesicles (hUCMSC-EVs) significantly enhance the bioavailability of the AuCu-Cur, promoting DNA replication, and promoting tissue repair via p-JNK pathway. In a rat tail needle puncture model, this system markedly alleviated IVDD. This study presents a promising approach to reverse the DNA damage-induced cellular senescence and IVDD, providing a repair strategy for addressing diseases associated with DNA damage and cellular senescence.